Ecotin-Like ISP of L. major Promastigotes Fine-Tunes Macrophage Phagocytosis by Limiting the Pericellular Release of Bradykinin from Surface-Bound Kininogens: A Survival Strategy Based on the Silencing of Proinflammatory G-Protein Coupled Kinin B-2 and B-1 Receptors
Autor(a) principal: | |
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Data de Publicação: | 2014 |
Outros Autores: | , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNIFESP |
Texto Completo: | http://repositorio.unifesp.br/handle/11600/37126 http://dx.doi.org/10.1155/2014/143450 |
Resumo: | Inhibitors of serine peptidases (ISPs) expressed by Leishmania major enhance intracellular parasitism in macrophages by targeting neutrophil elastase (NE), a serine protease that couples phagocytosis to the prooxidative TLR4/PKR pathway. Here we investigated the functional interplay between ISP-expressing L. major and the kallikrein-kinin system (KKS). Enzymatic assays showed that NE inhibitor or recombinant ISP-2 inhibited KKS activation in human plasma activated by dextran sulfate. Intravital microscopy in the hamster cheek pouch showed that topically applied L. major promastigotes (WT and Delta isp2/3 mutants) potently induced plasma leakage through the activation of bradykinin B-2 receptors (B2R). Next, using mAbs against kininogen domains, we showed that these BK-precursor proteins are sequestered by L. major promastigotes, being expressed at higher % in the Delta isp2/3 mutant population. Strikingly, analysis of the role of kinin pathway in the phagocytic uptake of L. major revealed that antagonists of B2R or B1R reversed the upregulated uptake of Delta isp2/3mutants without inhibiting macrophage internalization of WT L. major. Collectively, our results suggest that L. major ISP-2 fine-tunes macrophage phagocytosis by inhibiting the pericellular release of proinflammatory kinins from surface bound kininogens. Ongoing studies should clarify whether L. major ISP-2 subverts TLR4/PKR-dependent prooxidative responses of macrophages by preventing activation of G-protein coupled B2R/B1R. |
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Svensjo, ErikAlmeida, Larissa Nogueira deVellasco, LucasJuliano, Luiz [UNIFESP]Scharfstein, JulioUniversidade Federal do Rio de Janeiro (UFRJ)Universidade Federal de São Paulo (UNIFESP)2016-01-24T14:34:55Z2016-01-24T14:34:55Z2014-01-01Mediators of Inflammation. New York: Hindawi Publishing Corporation, 12 p., 2014.0962-9351http://repositorio.unifesp.br/handle/11600/37126http://dx.doi.org/10.1155/2014/143450WOS000344254200001.pdf10.1155/2014/143450WOS:000344254200001Inhibitors of serine peptidases (ISPs) expressed by Leishmania major enhance intracellular parasitism in macrophages by targeting neutrophil elastase (NE), a serine protease that couples phagocytosis to the prooxidative TLR4/PKR pathway. Here we investigated the functional interplay between ISP-expressing L. major and the kallikrein-kinin system (KKS). Enzymatic assays showed that NE inhibitor or recombinant ISP-2 inhibited KKS activation in human plasma activated by dextran sulfate. Intravital microscopy in the hamster cheek pouch showed that topically applied L. major promastigotes (WT and Delta isp2/3 mutants) potently induced plasma leakage through the activation of bradykinin B-2 receptors (B2R). Next, using mAbs against kininogen domains, we showed that these BK-precursor proteins are sequestered by L. major promastigotes, being expressed at higher % in the Delta isp2/3 mutant population. Strikingly, analysis of the role of kinin pathway in the phagocytic uptake of L. major revealed that antagonists of B2R or B1R reversed the upregulated uptake of Delta isp2/3mutants without inhibiting macrophage internalization of WT L. major. Collectively, our results suggest that L. major ISP-2 fine-tunes macrophage phagocytosis by inhibiting the pericellular release of proinflammatory kinins from surface bound kininogens. Ongoing studies should clarify whether L. major ISP-2 subverts TLR4/PKR-dependent prooxidative responses of macrophages by preventing activation of G-protein coupled B2R/B1R.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)PRONEXUniv Fed Rio de Janeiro, Inst Biofiis Carlos Chagas Filho, BR-21990400 Rio de Janeiro, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, BR-04044020 São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, BR-04044020 São Paulo, BrazilWeb of Science12engHindawi Publishing CorporationMediators of InflammationEcotin-Like ISP of L. major Promastigotes Fine-Tunes Macrophage Phagocytosis by Limiting the Pericellular Release of Bradykinin from Surface-Bound Kininogens: A Survival Strategy Based on the Silencing of Proinflammatory G-Protein Coupled Kinin B-2 and B-1 Receptorsinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UNIFESPinstname:Universidade Federal de São Paulo (UNIFESP)instacron:UNIFESPORIGINALWOS000344254200001.pdfapplication/pdf2243198${dspace.ui.url}/bitstream/11600/37126/1/WOS000344254200001.pdfdfeb64a3ac2c722c5fdfeadaec6ce7fcMD51open accessTEXTWOS000344254200001.pdf.txtWOS000344254200001.pdf.txtExtracted texttext/plain65667${dspace.ui.url}/bitstream/11600/37126/2/WOS000344254200001.pdf.txt05fc31abedb9514456a4cf7c93c4b810MD52open access11600/371262022-07-08 10:40:20.725open accessoai:repositorio.unifesp.br:11600/37126Repositório InstitucionalPUBhttp://www.repositorio.unifesp.br/oai/requestopendoar:34652022-07-08T13:40:20Repositório Institucional da UNIFESP - Universidade Federal de São Paulo (UNIFESP)false |
dc.title.en.fl_str_mv |
Ecotin-Like ISP of L. major Promastigotes Fine-Tunes Macrophage Phagocytosis by Limiting the Pericellular Release of Bradykinin from Surface-Bound Kininogens: A Survival Strategy Based on the Silencing of Proinflammatory G-Protein Coupled Kinin B-2 and B-1 Receptors |
title |
Ecotin-Like ISP of L. major Promastigotes Fine-Tunes Macrophage Phagocytosis by Limiting the Pericellular Release of Bradykinin from Surface-Bound Kininogens: A Survival Strategy Based on the Silencing of Proinflammatory G-Protein Coupled Kinin B-2 and B-1 Receptors |
spellingShingle |
Ecotin-Like ISP of L. major Promastigotes Fine-Tunes Macrophage Phagocytosis by Limiting the Pericellular Release of Bradykinin from Surface-Bound Kininogens: A Survival Strategy Based on the Silencing of Proinflammatory G-Protein Coupled Kinin B-2 and B-1 Receptors Svensjo, Erik |
title_short |
Ecotin-Like ISP of L. major Promastigotes Fine-Tunes Macrophage Phagocytosis by Limiting the Pericellular Release of Bradykinin from Surface-Bound Kininogens: A Survival Strategy Based on the Silencing of Proinflammatory G-Protein Coupled Kinin B-2 and B-1 Receptors |
title_full |
Ecotin-Like ISP of L. major Promastigotes Fine-Tunes Macrophage Phagocytosis by Limiting the Pericellular Release of Bradykinin from Surface-Bound Kininogens: A Survival Strategy Based on the Silencing of Proinflammatory G-Protein Coupled Kinin B-2 and B-1 Receptors |
title_fullStr |
Ecotin-Like ISP of L. major Promastigotes Fine-Tunes Macrophage Phagocytosis by Limiting the Pericellular Release of Bradykinin from Surface-Bound Kininogens: A Survival Strategy Based on the Silencing of Proinflammatory G-Protein Coupled Kinin B-2 and B-1 Receptors |
title_full_unstemmed |
Ecotin-Like ISP of L. major Promastigotes Fine-Tunes Macrophage Phagocytosis by Limiting the Pericellular Release of Bradykinin from Surface-Bound Kininogens: A Survival Strategy Based on the Silencing of Proinflammatory G-Protein Coupled Kinin B-2 and B-1 Receptors |
title_sort |
Ecotin-Like ISP of L. major Promastigotes Fine-Tunes Macrophage Phagocytosis by Limiting the Pericellular Release of Bradykinin from Surface-Bound Kininogens: A Survival Strategy Based on the Silencing of Proinflammatory G-Protein Coupled Kinin B-2 and B-1 Receptors |
author |
Svensjo, Erik |
author_facet |
Svensjo, Erik Almeida, Larissa Nogueira de Vellasco, Lucas Juliano, Luiz [UNIFESP] Scharfstein, Julio |
author_role |
author |
author2 |
Almeida, Larissa Nogueira de Vellasco, Lucas Juliano, Luiz [UNIFESP] Scharfstein, Julio |
author2_role |
author author author author |
dc.contributor.institution.none.fl_str_mv |
Universidade Federal do Rio de Janeiro (UFRJ) Universidade Federal de São Paulo (UNIFESP) |
dc.contributor.author.fl_str_mv |
Svensjo, Erik Almeida, Larissa Nogueira de Vellasco, Lucas Juliano, Luiz [UNIFESP] Scharfstein, Julio |
description |
Inhibitors of serine peptidases (ISPs) expressed by Leishmania major enhance intracellular parasitism in macrophages by targeting neutrophil elastase (NE), a serine protease that couples phagocytosis to the prooxidative TLR4/PKR pathway. Here we investigated the functional interplay between ISP-expressing L. major and the kallikrein-kinin system (KKS). Enzymatic assays showed that NE inhibitor or recombinant ISP-2 inhibited KKS activation in human plasma activated by dextran sulfate. Intravital microscopy in the hamster cheek pouch showed that topically applied L. major promastigotes (WT and Delta isp2/3 mutants) potently induced plasma leakage through the activation of bradykinin B-2 receptors (B2R). Next, using mAbs against kininogen domains, we showed that these BK-precursor proteins are sequestered by L. major promastigotes, being expressed at higher % in the Delta isp2/3 mutant population. Strikingly, analysis of the role of kinin pathway in the phagocytic uptake of L. major revealed that antagonists of B2R or B1R reversed the upregulated uptake of Delta isp2/3mutants without inhibiting macrophage internalization of WT L. major. Collectively, our results suggest that L. major ISP-2 fine-tunes macrophage phagocytosis by inhibiting the pericellular release of proinflammatory kinins from surface bound kininogens. Ongoing studies should clarify whether L. major ISP-2 subverts TLR4/PKR-dependent prooxidative responses of macrophages by preventing activation of G-protein coupled B2R/B1R. |
publishDate |
2014 |
dc.date.issued.fl_str_mv |
2014-01-01 |
dc.date.accessioned.fl_str_mv |
2016-01-24T14:34:55Z |
dc.date.available.fl_str_mv |
2016-01-24T14:34:55Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
Mediators of Inflammation. New York: Hindawi Publishing Corporation, 12 p., 2014. |
dc.identifier.uri.fl_str_mv |
http://repositorio.unifesp.br/handle/11600/37126 http://dx.doi.org/10.1155/2014/143450 |
dc.identifier.issn.none.fl_str_mv |
0962-9351 |
dc.identifier.file.none.fl_str_mv |
WOS000344254200001.pdf |
dc.identifier.doi.none.fl_str_mv |
10.1155/2014/143450 |
dc.identifier.wos.none.fl_str_mv |
WOS:000344254200001 |
identifier_str_mv |
Mediators of Inflammation. New York: Hindawi Publishing Corporation, 12 p., 2014. 0962-9351 WOS000344254200001.pdf 10.1155/2014/143450 WOS:000344254200001 |
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http://repositorio.unifesp.br/handle/11600/37126 http://dx.doi.org/10.1155/2014/143450 |
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eng |
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Hindawi Publishing Corporation |
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Hindawi Publishing Corporation |
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